Early detection is critical in providing curative therapies for the vast majority of solid malignancies. Recent data from our own group and others suggest that circulating tumor cells (CTCs) may be shed in significant numbers into the blood stream of patients with invasive but localized cancers. Dissemination of abnormal cells has even been reported in patients with preneoplastic breast lesions (DCIS). Together, these observations suggest that, rather than being rare and late events in the evolution of cancer, the presence of CTCs may be an early herald of tumor vascular invasion, preceding a considerable period of time for the eventual establishment of viable distant metastases. This concept provides a radical departure from current approaches to early cancer detection, which are based on either radiographic screening or the development of reliable serum proteomic approaches. Testing for the presence of bona fide CTCs in the circulation would constitute a very powerful tool for early detection of cancer, but also requires the development of highly sensitive and reliable technology. The current approaches to microfluidic CTC detection that we have developed have sufficient capability to detect the presence of CTCs in some patients with early cancers, but they need to be greatly enhanced in both sensitivity and throughput to become valid for eventual application to population screening. Here, we propose technological innovations to allow such sensitive and robust CTC detection strategies, making use of enhanced microfluidic isolation and capture (Aim 1), as well as molecular tools for quantitation of minimal CTC numbers (Aim 2). Human studies will be given priority and will provide a rigorous test of our technological innovations and biological discoveries. This is a philosophical decision in that the project investigators strongly believe that to achieve the Quantum Project vision of solving or profoundly improving a specific health condition using technology-driven approaches in a time period of 5 years, the project must have a sharp focus on real systems at the onset of the program We propose a graded clinical application of these developing technologies, first in patients with known localized lung or breast cancer, and then in patients with newly diagnosed suspicious radiographic lesions that have been selected for biopsy (Aim 3). If successful, the combined bioengineering and molecular approaches proposed here would lead to indications for large scale screening studies in patients with environmental or genetic susceptibility to lung or breast cancers. Together, we have established a multidisciplinary team of researchers focused on extending CTC detection technologies to the challenge of early detection of invasive but localized cancers, with the potential for revolutionary approaches to cancer prevention.